Although IFN-gamma-activated macrophages are capable of destroying mycobacteria, most macrophages within a tuberculoid granuloma are maintained in an anergic state. Understanding the mechanism of macrophage anergy will allow development of both preventative and curative strategies for the-treatment of tuberculosis and other mycobacterial diseases. The hypothesis to be tested is that trehalose dimycolate (TDM), a prominent component of the mycobacterial cell wall, actively interferes with IFN-gamma signaling and is an important mechanism by which these bacilli modulate macrophage behavior. The specific aims of this proposal are: 1. To identify the macrophage receptor for TDM or the mechanism by which TDM triggers macrophage signaling, and determine how the mode of TDM presentation affects this process. 2. To dissect the TDM proinflammatory signaling pathway in the macrophage and determine how this pathway subverts the IFN-gamma signaling pathway. Techniques to be employed during this study include: enzyme-linked immunosorbent assay, electron mobility shift assay, quantitative real-time polymerase chain reaction, immunoblot, affinity isolation, microarray analysis, transfection, confocal microscopy, and lipid raft analysis.